Systematic Review and Meta-Analysis: Lack of Early Improvement Predicts Inefficacy of Antipsychotics for Schizophrenia in Adolescents.

OBJECTIVE: This study sought to inform the duration of an antipsychotic trial for children and adolescents with schizophrenia before considering medication changes. METHOD: We searched CENTRAL, Embase, and PubMed as of January 2025 and ClinicalTrials.gov for double-masked randomized clinical trials (RCTs) of antipsychotics for children and adolescents with schizophrenia. The main outcome was overall symptoms of schizophrenia. We estimated the average trajectory of efficacy over time by pooling standardized mean differences (SMDs) of antipsychotics against placebo at each available time point with random-effects meta-regression. We also evaluated the predictive value of lack of early improvement (< 20% symptoms reduction at two weeks) on non-response and non-remission at the endpoint. RESULTS: From 3,106 retrieved records, 14 RCTs involving 3,115 participants aged 8-19 years (age mean [SD] 15.4 [1.5]; 58% male, 65% White participants) were included. On average, there were gradual gains in efficacy from week 1 (SMD [95% confidence interval, CI] -0.15 [-0.23, -0.07]) to week 4 (-0.46 [-0.58, -0.33]), with fewer additional gains later (week 6: -0.55 [-0.7, -0.39]; week 8: -0.57 [-0.8, -0.34]). Furthermore, lack of early improvement reliably predicted non-response (specificity [95% CI]: 82% [75%, 87%]; positive predictive value [PPV]: 91%) and non-remission (68% [58%, 76%]; 76%) at the endpoint. CONCLUSION: Most of the effects attributed to antipsychotics may be observed within the first four weeks of treatment. Children and adolescents who do not show some improvement during the first two weeks of treatment may be more likely to be non-responders and non-remitters at the endpoint.